Bicyclic 1-aza-cycloalkanes, mixture of isomers, or individual isomers, or their pharmacologically tolerated acid additive salt

 

(57) Abstract:

Usage: as substances with holinoliticheskoy action. The essence of the invention: bicyclic product I-azacycloheptane General formula-CH2-, where R is lower alkyl, unsubstituted or substituted furan, thiophene or indazole; alkenyl with 3 to 6 carbon atoms; quinil with 3 to 6 carbon atoms; phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or by halogen; benzyl, unsubstituted or substituted by halogen; pyridyl; pyrimidinyl, A, B and C are independently from each other mean or a simple bond, n is 0 or 1, the mixture of their isomers or individual isomers, or their pharmacologically acceptable salts. table 4.

The invention relates to new compounds with pharmacological activity, in particular bicyclic 1-Aza-cycloalkanes General formula

(I) where R is lower alkyl, unsubstituted or substituted furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; quinil with 3-6 carbon atoms; phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or by halogen; benzyl, unsubstituted or substituted by halogen; pyridyl; pyrimidinyl;

A, b and C independently of one another denote-CH2or a simple bond; itemnum salts, showing holinoliticheskoy properties.

New connections can be obtained due to the fact that

a) compound of General formula

(II) where a, b, C and n have the above meanings; Z protective group is subjected to deprotonation and subsequent interaction with the compound of General formula

Y-R1(III) where R1lower alkyl, unsubstituted or substituted furan, thiophene or imidazole, alkenyl with 3-6 carbon atoms, quinil with 3-6 carbon atoms, phenyl, phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or halogen; Y is easy tsepliaeva group, and removing the protective group z

b) the compound of General formula

(IV) where a, b, C and n have the above meanings, is subjected to the interaction with the compound of General formula

HO-R2(V) where R2benzyl, unsubstituted or substituted by halogen, pyridyl, pyrimidinyl, in the presence of triphenylphosphine and complex Olkiluoto ester of azodicarboxylic acid.

Obtained according to (a) and (b) the target product is isolated in free form or in the form of a racemate or enantiomer or diastereomer mixture or diastereomers or in the form of a pharmacologically tolerable acid additive salt, preferably in the form of Methodi the residents, as, for example, dimethylformamide, tetrahydrofuran, dioxane, etc., while the deprotonation preferably carried out at room temperature or slightly elevated temperature, followed by alkylation is preferably carried out while cooling with ice.

As reagents for the implementation of the deprotonation preferably using sodium hydride, sodium amide, alkali metal alcoholate, such as, for example, tert-butyl potassium.

The reaction according to (b) is usually carried out at room temperature in inert organic solvents.

Compounds of General formula (I) have valuable pharmacological properties. For example, in experiments on binding to receptors of compounds showing affinity for the muscarinic receptors, muscarine-agonistic offsets GTP.

Studies on the binding of receptors was carried out according to known methods.

Studies on the binding of receptors is shown below.

Radioligand: iodide L(+)CIS-[2-methyl-3N]-N,N,N-trimethyl-1,3-dioxolane-4-meta - ammonia (trade product NET-647 foreign companies NEN, GB).

Body: the Cortex of the rat brain Connection Factor Ki [nmol/1]

in example 2 89 4 120 is s for the treatment of diseases with insufficient function of the cholinergic system.

In the pharmacological experiments new compounds suitable for treatment of the following diseases: Alzheimer's disease, senile dementia, cognitive disorders. In addition, they can also be used to improve the functional capacity of memory.

Quaternary compounds of the formula (I) are particularly suitable for peripheral applications, such as, for example, for the treatment of glaucoma.

P R I m e R 1. 3 Propargyloxy-1-azabicyclo[2,2,1]heptane. In the atmosphere of nitrogen 5.5 g (0.05 mol) of 1-azabicyclo[2,2,1]heptane-3-ol are dissolved in 150 ml of absolute tetrahydrofuran and mixed with 50 ml of 1M complex of borane and tetrahydrofuran at 0aboutC. After completion of the process of adding the specified complex is stirred for 1 h at room temperature, concentrated to dryness, the residue absorbed in a saturated solution of sodium chloride and extracted with dichloromethane. The combined organic phases are dried and concentrated, the residue is dissolved in 120 ml of absolute tetrahydrofuran in a nitrogen atmosphere portions mixed with 2,08 g (0,052 mol) of sodium hydride. After one hour the reaction mixture was cooled to 0aboutWith, and when this temperature drops add 17,55 g propylbromide in the form of a 50% aqueous solution of Tetra the structure of ethanol, concentrated, the residue is absorbed in a saturated solution of sodium chloride and extracted with dichloromethane. After drying and concentrating the combined organic phases receive oil, shepherd in high vacuum (TCL45-46aboutC). To obtain fumarata use one equivalent of fumaric acid, recrystallized from a mixture of ethanol and simple ether and dried in vacuum. Obtain 2.1 g of the above compound in the form of colorless crystals with so pl. 121-123aboutC.

1H-NMR (250 MHz, CD3OD, TMS*): of 6.68 (2H, s, fumaric acid); 4,47 (1H, m, H-3); IS 4.21 (2H, m, CH2-8); to 3.73-2,86 (7H, m, CH2-2,6,7; H-4); 2,95 (1H, t, J 3 Hz, H-9); 2,30; A 1.96 (2H, m, CH2-5).

*) tetramethylsilane

P R I m m e R 2. 3 Phenoxy-1-azabicyclo[2,2,1]octane. 3,82 g (0.03 mol) of 3-oxyhemoglobin, 2,82 g (0.03 mol) of phenol, of 7.96 g (0.03 mol) of triphenylphosphine and with 5.22 g (0.03 mol) of a compound diethyl ester of azodicarboxylic acid are dissolved in 150 ml of absolute tetrahydrofuran and stirred for two days at room temperature. Concentrated to dryness, the residue is absorbed in 20 ml of 6N hydrochloric acid and 50 ml of water and extracted with simple ether. The aqueous phase is alkalinized and extracted by shaking with ethyl acetate, the combined e is (C).

1H-NMR (250 MHz, CDCl3, TMS): 7,26; 6,87 (5H, m, aryl-H); 4,36 (1H, m, H-3); 3,34 2.63 IN (6N, m, CH2-2,6,7); 2,19-of 1.27 (5H, m, CH-4; CH2-5,8).

The base was transferred to the ethanol solution of fumarate, which precipitated a simple ether and recrystallized from acetonitrile. Obtain 4.1 g of colorless crystals with so pl. 122-124aboutC.

P R I m e R 3. (+)- and (-)-3-(propargyloxy)-1-azabicyclo-[2,2,2] octane.

a) (+)-3-(propargyloxy)-1-azabicyclo[2,2,2] -octane. 5.6 g of the hydrochloride of (+)-3-hinoklidilkarbinola, 1,32 g of borane, sodium and 100 ml of tetrahydrofuran is stirred over night. From the filtrate to remove the solvent, the residue is absorbed in a complex ethyl ester of acetic acid and the resulting solution was washed with a saturated solution of salt. After drying and removal of solvent remain 3.4 g of the complex (+)-3-giocodigitale and borane as a yellow oil.

3.4 g of the specified complex and 2,63 g of 60% sodium hydride is stirred in 100 ml of tetrahydrofuran for 30 min at room temperature, then the reaction product is subjected to interaction with 4,89 g 80% propylbromide and stirred for further 6 hours, the Reaction mixture was carefully decomposed by alcohol, the solvent is removed, sodium acid, and again remove the solvent. For the destruction of the protective boranova group balance absorbed in 50 ml of acetone and mixed with 20 ml of 3 N hydrochloric acid during the night. After evaporation of acetone, the aqueous phase is washed with complex ethyl ester acetic acid, alkalinized with potassium and extracted with complex ethyl ester of acetic acid. The resulting extraction residue is subjected to flash chromatography on silica gel using as eluent a complex ethyl ester acetic acid, methanol and ammonia in the ratio of 85:15:1. Get 4.3 g propargilovyh ether, which in the environment of alcohol is transferred to the fumaric salt by adding the calculated amount of fumaric acid. Salt is subjected to presideny from a mixture of alcohol and simple diethyl ether. Get 3,9 g so pl. 132-133aboutC. []D20+28,47about(C 1, methanol).

b) (-)-3-(propargyloxy)-1-azabicyclo[2,2,2]octane.

Similarly, stage (a) in (-)-3-hinkleyville impose protective boranova group, are substantial propylbromide and after removing the protective boranova group free base was transferred to fumarate with, etc., 132-133aboutC. []D20-28,42about(C 1, methanol).

Similarly, note the hydroxy)-1-azabicyclo[2,2,2]octane.

14.1 g (0.1 mol) of 3-hydroxy-1-azabicyclo[2,2,2]octane in the form of a complex with borane subjected to interaction with 4 g of sodium hydride as a 60% dispersion in oil in medium 140 ml of dimethylformamide at room temperature. After the hydrogen evolution reaction mixture is mixed with a solution of 14.28 g (0.12 mol) of propargylamine in 10 ml of toluene under ice cooling, and then stirred at room temperature for 3 hours, add 5 ml of ethanol and concentrated in vacuo in a rotary evaporator. The residue is partitioned between 10% sodium chloride solution and diethyl ether. The organic phase is dried over anhydrous sodium sulfate and concentrated. The remaining dark brown oil mixed with 75 ml of tetrahydrofuran and 15 ml of acetate. To the resulting solution under ice cooling was added dropwise 30 ml of 4 N. hydrochloric acid. The reaction mixture is left to stand for one hour at room temperature, after which the organic solvent is distilled off. The residue is diluted with a small amount of water and successively extracted with petroleum ether and diethyl ether. The aqueous phase is alkalinized 40% potassium carbonate solution and extracted with diethyl ether. The ether solution is dried over anhydrous sodium sulfate and out at fumarate by adding an equivalent of fumaric acid. So pl. 138-140about(From a mixture of ethanol and diethyl ether).

Calculated C 59,77; H for 6.81; N TO 4.98

C10H15NO x C4H4O4(281,31)

Found, C 59,86; H 6,76; N 4,95.

P R I m e R 37. Repeat example 35 with the difference that instead of propylbromide use n-propyl bromide. Get 3-(n-propyloxy)-1-azabicyclo[2.2.2]octane in the form of fumarata with so pl. 120-121about(From acetonitrile).

Calculated C 55,97; H 7,34; N 4,08

C10H19NO x 1.5 C4H4O4(343,38)

Found, C 55,67; H 7,51; N 4.09 To.

Bicyclic 1-Aza-cycloalkanes General formula

< / BR>
where R is lower alkyl, unsubstituted or substituted furan, thiophene or imidazole C3-C6alkenyl, C3-C6-quinil, phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or halogen, benzyl, unsubstituted or substituted by halogen, pyridyl, pyrimidinyl;

A, B and C independently of one another-CH2or a simple bond;

n is 0 or 1,

the mixture of isomers or individual isomers, or their pharmacologically tolerated acid additive salts with holinoliticheskoy properties.

 

Same patents:

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36 cl, 164 ex

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34 cl, 2 tbl, 104 ex

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25 cl, 1 tbl, 165 ex

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20 cl, 1 tbl, 184 ex

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FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

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